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168 Part IV: Molecular and Cellular Hematology Chapter 12: Epigenetics 169

A major concept in histone modification biology is dynamic modifications for days following withdrawal of the initial stimulus.
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reversibility, termed write, read, erase. 1,15,16 “Writing” involves the enzy- Importantly, the retention of these modifications is correlated with a
matic addition of a covalent modification to an amino acid, within a more robust or rapid activation in response to a second stimulus. Thus,
particular protein sequence context. “Reading” involves the ability of chromatin states can confer a memory of prior transcriptional states
a second protein/domain to bind that modification, within a particu- that shapes future response. Here, one can infer within Fig. 12–2 that
lar protein sequence context, defining the impact of the modification. following activation, this system does not return to the initial repressed
“Erasing” involves the removal of the covalent modification, within a state, but rather to an intermediate “poised” state where histone modifi-
particular sequence context, regenerating the prior/initial state. These cations are retained at the enhancer.
concepts are actually quite general, and can be applied widely in
protein signal transduction biology, with this terminology simply hav- DNA METHYLATION AND
ing become popularized in the chromatin field. Nevertheless, these
terms are quite useful for framing histone modification cycles that DEMETHYLATION PRINCIPLES
accompany transcription cycles. One illustrative example is the addi-
tion of histone acetylation by histone acetyltransferase (HAT) enzymes, DNA METHYLATION
the binding of acetylated histone tails by the bromodomain (present DNAme is a major component of epigenetic regulation in mammals,
in SWI/SNF remodelers and certain chromatin modifiers), 17,18 and the with central roles in gene and transposon silencing, imprinting, and
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removal of acetylation by HDAC enzymes. Finally, although this chap- X-chromosome inactivation. Furthermore, DNAme can predispose
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ter discusses histone modifications and modifiers, histone modifiers to cancer by at least two routes: first, through the improper placement
often also modify additional chromatin proteins, including proteins of focal DNAme, leading to the silencing of tumor-suppressor genes;
that contain “histone mimic” regions. Although beyond the scope of second, through hypomethylation of the genome, causing genome
this chapter, those chromatin modifications often go through similar instability. Here, basic principles of DNAme and demethylation are
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“write, read, erase” cycles to enable additional layers of protein recruit- first discussed, with a later section “Epigenetic and Hematologic Malig-
ment and release within a chromatin process. nancies” focusing on their misregulation in hematologic malignancies.
DNAme primarily involves cytosine methylation in a CpG context,
TRANSCRIPTION FACTOR-CHROMATIN and in mammalian genomes the vast majority (>85 percent) of such
cytosines are methylated. DNAme is conducted by DNMTs, involving
MODIFIER PROGRAMS FOR the de novo enzymes DNMT3a and DNMT3b (which can methylate
DIFFERENTIATION unmethylated regions) or by the maintenance enzyme DNMT1, which
partners with ubiquitin-like with PHD and ring finger domains factor
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Within the context above, a common theme in cell differentiation is (UHRF1) to fully methylate hemimethylated CGs during replication.
waves of transcription factor–chromatin modifier interactions that DNAme confers silencing through two modes. First, DNAme inhibits
define the current chromatin and transcription state, and also help pre- or prevents the binding of many transcription factors with CG sites
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pare the enhancers and promoters of genes needed for future states/cell in their consensus binding sequence, including cMyb, cMyc, E2F-
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types (see Fig. 12–2). Signaling systems inform cellular differentiation family, nuclear factor-κB, CREB-family, ETS-family, and AP2
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decisions, and define the next differentiation state by affecting transcrip- factors. Second, certain methyl-domain binding (MBD) proteins (e.g.,
tion factor activity and their interaction with chromatin factors, creating MBD1, MBD2, MECP2) bind to methylated CpG sites and can recruit
a forward loop. Quite often, the transcription factor–chromatin modifier both HDAC, repressive HMTs, and CHD-family remodelers (e.g.,
interactions of the new state (and cell type) also feedback to inhibit the NuRD) to establish and maintain repression. 30
prior program, as well as alternative differentiation programs, so as to Although most genomic CGs are methylated, mammalian genomes
ensure the proper developmental trajectory. An example that illustrates are punctuated by small regions (250 bp to 2 kb) where DNAme is nota-
part of this program in action involves the transition between HSCs and bly absent, and these regions are strongly correlated with a high relative
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erythroid progenitors, which involves a switch in the abundance and density of CG bases, termed CpG islands. (CpG islands are regions that
activity of transcription factors (e.g., GATA2 to GATA1) and histone have avoided the strong CG depletion that has occurred over the rest
methyltransferase (HMT) paralogs (e.g., enhancer of zeste homologue 2 of the genome, as methylated cytosine can spontaneously deaminate to
[EZH2] to EZH1). 20,21 This switch serves to repress a set of stem-related create uracil). Thus, methylated CGs are absent in regions where CGs
genes while activating a set of pro-differentiation genes. By extension, are dense, a counterintuitive observation that underscores that CG-rich
many studies show that loss-of-function mutations in chromatin fac- regions must attract active mechanisms to either prevent DNMT activ-
tors can prevent developmental transitions, and if this block occurs at a ity or remove DNAme (see section “TET Proteins and Active DNA
highly proliferative progenitor stage, it can predispose to cancer. Demethylation”). CpG islands reside in the promoters of most genes
that are constitutively transcribed, such as housekeeping/metabolic
genes, and these islands remain unmethylated under virtually all con-
EPIGENETICS AND MEMORY: ditions and cell types. However, CpG islands vary in size and composi-
TRAINED IMMUNITY tion; those of intermediate CG density are often found at developmental
genes; notably, these intermediate CpG islands are typically unmeth-
Trained immunity refers to a type of memory in the innate immune ylated in stem cells, but undergo developmentally regulated DNAme
system where genes that have been activated in the past (via infection to confer silencing in cell types where their expression might confer
or vaccination, termed stimulation) are “primed” for a more rapid and/ alternative fates. Notably, CpG islands often contain binding sites for
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or robust future response. Here, prior to initial stimulation, monocytes transcription factors; for those transcription factors that display methy-
and macrophages bear “latent” enhancers neighboring proinflamma- lation-sensitive binding (listed above), a lack of DNAme in these regions
tory genes, which lack histone modifications. Following stimulation, can permit their binding, whereas CpG island methylation can prevent
these latent enhancers acquire histone modifications (e.g., H3K4me and binding. Taken together, proper regulation of DNAme is critical, as the
H3K27ac) that are correlated with gene activation and maintain those improper placement of focal DNAme can lead to gene silencing.

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